Frataxin
Frataxin is a small protein (Isoform 1: NCBI NM_000144.4, NP_000135 (210 aa), SEQ ID NO: 1; Isoform 2: NM_181425, NP_852090 (196 aa), SEQ ID NO: 2; Isoform 3: NM_001161706, NP_001155178, (171 aa), SEQ ID NO: 3; Uniprot Q16595; ENTREZ 2395; Ensembl ENSG00000165060; OMIM: 606829) found in cells throughout the body, with the highest levels in tissues with a high metabolic rate including heart, neurons, spinal cord, liver, pancreas (Langerhans cells), and muscles used for voluntary movement (skeletal muscles). Within cells, frataxin is found in mitochondria. It promotes the biosynthesis of heme as well as the assembly and repair of iron-sulfur clusters by delivering Fe2+ to proteins involved in these pathways. It also plays a primary role in the protection against oxidative stress through its ability to catalyze the oxidation of Fe2+ to Fe3+ and to store large amounts of the metal in the form of a ferrihydrite mineral. It is processed in two steps by mitochondrial processing peptidase (MPP). MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to a mature protein. Thus, in cells, 3 forms exist. For isoform 1, these forms are frataxin (56-210); frataxin (78-210) and frataxin (81-210), which is the main form of mature frataxin (Schoenfeld et al. 2005).
Friedreich Ataxia
Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative and cardiac disease, is caused by a trinucleotide repeat expansion mutation in the first intron of the frataxin gene (FXN), which is located on the long arm of chromosome 9 (Location UCSC: 71,650,175 to 71715094 (64,920 bp; 9q21.11)). The mutation leads to a reduced expression of the frataxin mRNA and protein. Frataxin is essential for proper functioning of mitochondria. As noted above, it is involved in the removal of iron and when frataxin is reduced, iron builds up and causes free radical damage. Nerve and muscle cells are particularly sensitive to these deleterious effects. FRDA occurs in 1 in 50,000 persons in European populations but is much more frequent in the province of Quebec in Canada, because of founder effects. Males and females are affected equally. In the classic form, FRDA symptoms appear during or before the second decade of life. It is characterized by ataxia, areflexia, loss of vibratory sense and proprioception and dysarthria (Pandolfo 2012). Moreover, FRDA patients often have systemic involvement, with cardiomyopathy, diabetes mellitus and scoliosis. Early death can result from cardiomyopathy or associated arrhythmias. Degeneration of the dorsal root ganglion cells, their ascending dorsal spinal columns and the spinocerebellar tracts results in a progressive sensory ataxia. Many patients are wheelchair bound by their third decade. Associated oculomotor problems include optic atrophy, square-wave jerks and difficulty with fixation. Importantly, cognitive abilities are relatively spared. However, many patients suffer from depression.
The mutation responsible for FRDA is an unstable hyper-expansion of a GAA triplet repeat located in the first intron of the frataxin gene (Campuzano et al. 1996). In normal subjects, there are 6-34 repeats, whereas in FRDA patients there are 150 or more repeats. Patients with fewer repeats (150-200) have milder symptoms than those with longer sections with more triplet repeats (350 to 650). In some severely affected patients there are up to 1700 repeats. Since the frataxin gene mutation is located in an intron, it does not alter the amino acid sequence of the frataxin protein. There are 2-3% of FRDA patients who have a point mutation, either a missense or a non-sense. Some patients with a missense mutation have less severe symptoms because the mutated protein in still functional.
Pathological Mechanism
The pathological mechanisms have been reviewed by Pandolfo et al. (Pandolfo 2012). The repeated GAA triplets cause modifications in DNA methylation and the formation of triplex in the DNA, i.e., unusual non-B DNA conformations, which decrease transcription and subsequently reduce levels of the encoded protein, frataxin (level of expression is 5 to 35% of normal; (Coppola et al. 2006, Coppola et al. 2009)). Iron accumulation in mitochondria is mainly observed in the cardiac cells of patients and in the dentate nucleus of the brain. It is associated with oxidative damage. The reduction of frataxin leads to changes in gene expression of 185 different genes (Coppola et al. 2006, Coppola et al. 2009). Thus the reduction of frataxin has profound effects on several metabolic pathways and the correction of only one of these pathways by a drug may not be ideal.
Several strategies have been developed for treating Friedreich ataxia. These fall generally into the following 5 categories: 1) use of antioxidants to reduce the oxidative stress caused by iron accumulation in the mitochondria; 2) use of iron chelators to remove iron from the mitochondria; 3) use of Histone Deacetylase Inhibitors (HDACIs) to prevent DNA condensation and permit higher expression of frataxin; 4) use of molecules such as cisplatin, 3-nitroproprionnic acid (3-NP), Pentamidine or erythropoietin (EPO) to boost frataxin expression; and 5) gene therapy
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.